Article

Molecular recognition of transcriptional repressor motifs by the WD domain of the Groucho/TLE corepressor.

Developmental Genetics Laboratory, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.
Molecular Cell (impact factor: 14.18). 07/2006; 22(5):645-55. DOI:10.1016/j.molcel.2006.04.024 pp.645-55
Source: PubMed

ABSTRACT The Groucho (Gro)/TLE/Grg family of corepressors operates in many signaling pathways (including Notch and Wnt). Gro/TLE proteins recognize a wide range of transcriptional repressors by binding to divergent short peptide sequences, including a C-terminal WRPW/Y motif (Hairy/Hes/Runx) and internal eh1 motifs (FxIxxIL; Engrailed/Goosecoid/Pax/Nkx). Here, we identify several missense mutations in Drosophila Gro, which demonstrate peptide binding to the central pore of the WD (WD40) beta propeller domain in vitro and in vivo. We define these interactions at the molecular level with crystal structures of the WD domain of human TLE1 bound to either WRPW or eh1 peptides. The two distinct peptide motifs adopt markedly different bound conformations but occupy overlapping sites across the central pore of the beta propeller. Our structural and functional analysis explains the rigid conservation of the WRPW motif, the sequence flexibility of eh1 motifs, and other aspects of repressor recognition by Gro in vivo.

0 0
 · 
0 Bookmarks
 · 
24 Views
  • Article: Genome-Wide Microarrray Analysis Reveals Roles for the REF-1 Family Member HLH-29 in Ferritin Synthesis and Peroxide Stress Response.
    Thanh K Quach, Han Ting Chou, Kun Wang, Gaolin Zheng Milledge, Casonya M Johnson
    [show abstract] [hide abstract]
    ABSTRACT: In Caenorhabditis elegans, the six proteins that make up the REF-1 family have been identified as functional homologs of the Hairy/Enhancer of Split (HES) proteins. These transcription factors act in both Notch dependent and Notch-independent pathways to regulate embryonic events during development; however, their post-embryonic functions are not well defined. As a first step toward understanding how the REF-1 family works together to coordinate post-embryonic events, we used gene expression microarray analysis to identify transcriptional targets of HLH-29 in L4/young adult stage animals. Here we show that HLH-29 targets are genes needed for the regulation of growth and lifespan, including genes required for oxidative stress response and fatty acid metabolism, and the ferritin genes, ftn-1 and ftn-2. We show that HLH-29 regulates ftn-1 expression via promoter sequences upstream of the iron-dependent element that is recognized by the hypoxia inducible factor, HIF-1. Additionally, hlh-29 mutants are more resistant to peroxide stress than wild-type animals and ftn-1(RNAi) animals, even in the presence of excess iron. Finally we show that HLH-29 acts parallel to DAF-16 but upstream of the microphthalmia transcription factor ortholog, HLH-30, to regulate ftn-1 expression under normal growth conditions.
    PLoS ONE 01/2013; 8(3):e59719. · 4.09 Impact Factor
  • Article: Cooperating transcription factors mediate the function of estrogen receptor.
    Elisa Fiorito, Madhumohan R Katika, Antoni Hurtado
    [show abstract] [hide abstract]
    ABSTRACT: Estrogen receptor (ER) is a hormone-regulated transcription factor that controls cell division and differentiation in the ovary, breast, and uterus. The expression of ER is a common feature of the majority of breast cancers, which is used as a therapeutic target. Recent genetic studies have shown that ER binding occurs in regions distant to the promoters of estrogen target genes. These studies have also demonstrated that ER binding is accompanied with the binding of other transcription factors, which regulate the function of ER and response to anti-estrogen therapies. In this review, we explain how these factors influence the interaction of ER to chromatin and their cooperation for ER transcriptional activity. Moreover, we describe how the expression of these factors dictates the response to anti-estrogen therapies. Finally, we discuss how cytoplasmatic signaling pathways may modulate the function of ER and its cooperating transcription factors.
    Chromosoma 11/2012; · 3.85 Impact Factor
  • Source
    Article: SUMOylated SoxE factors recruit Grg4 and function as transcriptional repressors in the neural crest
    Pei-Chih Lee, Kimberly M. Taylor-Jaffe, Kara M. Nordin, Maneeshi S. Prasad, Rachel M. Lander, Carole LaBonne
    [show abstract] [hide abstract]
    ABSTRACT: A growing number of transcriptional regulatory proteins are known to be modified by the small ubiquitin-like protein, SUMO. Posttranslational modification by SUMO may be one means by which transcriptional regulatory factors that play context-dependent roles in multiple processes can be regulated such that they direct the appropriate cellular and developmental outcomes. In early vertebrate embryos, SUMOylation of SoxE transcription factors profoundly affects their function, inhibiting their neural crest–inducing activity and promoting ear formation. In this paper, we provide mechanistic insight into how SUMO modification modulates SoxE function. We show that SUMOylation dramatically altered recruitment of transcriptional coregulator factors by SoxE proteins, displacing coactivators CREB-binding protein/p300 while promoting the recruitment of a corepressor, Grg4. These data demonstrate that SoxE proteins can function as transcriptional repressors in a SUMO-dependent manner. They further suggest a novel multivalent mechanism for SUMO-mediated recruitment of transcriptional coregulatory factors.
    The Journal of Cell Biology 09/2012; 198(5):799-813. · 10.26 Impact Factor

Show more

Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

C-terminal WRPW/Y motif
 
central pore
 
divergent short peptide sequences
 
Drosophila Gro
 
eh1 motifs
 
functional analysis
 
Gro)/TLE/Grg family
 
human TLE1
 
internal eh1 motifs
 
markedly different
 
missense mutations
 
molecular level
 
repressor recognition
 
rigid conservation
 
sequence flexibility
 
transcriptional repressors
 
two distinct peptide motifs
 
WD domain
 
wide range
 
WRPW motif